The present invention provides a vaccine against chronic diseases such as a bacterial, viral or parasitic infection or cancer, a method of making such vaccines and prophylaxis and treatment of chronic disease.
Compared to the limited number of diseases where vaccines are currently available, a very large number have so far escaped attempts to develop efficient vaccines. A common characteristic for many of these infectious diseases as well as cancer is that they develop slowly and manifest themselves as chronic diseases where the disease is maintained for years in the face of an existing host immune response. This often eventually results in immunopathology that is some cases, such as Chlamydia trachomatis, is the real cause of the human disease such as inflammatory scarring of the oviduct resulting in infertility. For some diseases such as Mycobacterium (M.) tuberculosis infection (TB), a vaccine exists. However, while the vaccine may prevent the acute manifestations of the disease, the bacteria is not cleared and a chronic or latent disease is established. TB runs essentially through 3 phases. During the acute phase, the bacteria proliferate in the organs, until the immune response increases to the point at which it can control the infection, whereupon the bacterial load peaks and starts declining. After this, a chronic or latent phase is established where the bacterial load is kept stable at a low level. In this phase M. tuberculosis goes from active multiplication to a state of slow or non-replicating persistence. In some cases such as TB, the infection can suddenly reactivate and overt disease will result. The factors that lead to this reactivation are largely unknown. In other cases such as Chlamydia, the infection may remain a symptomatic but the ongoing inflammatory process cause later clinical manifestations such as infertility.
The immune response to many of these difficult diseases includes both humoral and cell-mediated immunity (CMI) components. The CMI response is directed to a hierarchy of T-cell antigens and epitopes from the pathogen. The epitopes are amino acid (aa) stretches of 7-9 aa (MHC I) and 12-15 aa (MHC II) (1). In chronic viral disease such as human immunodeficiency virus (HIV), and chronic bacterial disease such as TB, as well as in cancer, the hierarchy of epitope responses change over time and responses to a few immunodominant epitopes which gradually constitute a large part of the total T-cell response, whereas a large number of other epitopes that all have the potential to bind the MHC class I or II antigen presentation molecules are subdominant or even cryptic resulting in T-cell responses at levels close to or below the detection level (2-6). If induced by vaccination (without competition from dominant epitopes), responses to such subdominant epitopes have been reported to be protective (e.g., in TB (7)), indicating that the epitopes are indeed expressed during the natural infection and can be recognized by effector cells on the invading pathogen. Studies indicate a major concern for current vaccine development is that subdominant epitope responses may have advantages compared to responses to immunodominant epitopes in HIV where escape mutants lack immunodominant epitopes and are therefore not seen by the immune system (8).
The utilization of subdominant T-cell epitopes in the design of vaccines has so far been hampered by two major roadblocks: i) the need for a large panel of different epitopes to cover a diverse human population due to the variation of individual epitopes recognized by individuals with different HLA composition; ii) the need to identify subdominant epitopes to which only low-level T-cell responses close to or below the detection level of immunological assays (e.g., the enzyme-linked immunospot (ELISPOT) assay) are found.
Olsen, et al. (7) describes that a vaccine based on one subdominant epitope of ESAT6 can protect against TB. However, a mix of overlapping peptides spanning the entire region of ESAT6 was not used in this study.
In International Patent Application Publication No. WO 01/016163, a vaccine against virus comprising a peptide mix consisting of peptides that activate T cells regardless of their HLA genotype is described. This application teaches the use of peptide mixes from Hepatitis B to enable a broad coverage when applied for the vaccination of a genetically diverse human population thereby circumventing the non-responders found when immunizing with single peptides. This invention does not teach the peptide driven expansion of T cells directed against subdominant T-cell epitopes relevant for the preventive and therapeutic vaccination against chronic bacterial diseases as taught in the present invention.
In International Patent Application Publication No. WO 03/011331, a prime-boost vaccine is disclosed. To prevent an increased response to dominant epitopes and decreased response to subdominant epitopes, priming is achieved by a DNA or viral vector encoding a string of epitopes. Following the priming stage, the epitopes are used individually, in separate constructs or carried on separate vehicles, to boost the response as opposed to being administered as a single poly-epitope DNA or viral construct.